Synthesis of the napalilactone and pathylactone A spirocyclic skeleton

Article abstract of DOI:10.1016/S0040-4039(01)02141-4

The spirolactone core of napalilactone and pathylactone A was synthesized in five steps from 2-methyl-2-cyclohexen-1-one or 2,3-dimethyl-2-cyclohexen-1-one. This spirolactone contains all of the carbon atoms and three of the four stereocenters of napalilactone and pathylactone A.

Full text of DOI:10.1016/S0040-4039(01)02141-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 221–224
Synthesis of the napalilactone and pathylactone A
spirocyclic skeleton†
James R. Vyvyan,a,* Courtney A. Rubensa and Jason A. Halfenb,‡
aDepartment of Chemistry, Western Washington University, Bellingham, WA 98225-9150, USA
bDepartment of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, WI 54701, USA
Received 18 September 2001; accepted 30 October 2001
Abstract—The spirolactone core of napalilactone and pathylactone A was synthesized in five steps from 2-methyl-2-cyclohexen-1-
one or 2,3-dimethyl-2-cyclohexen-1-one. This spirolactone contains all of the carbon atoms and three of the four stereocenters of
napalilactone and pathylactone A. © 2002 Elsevier Science Ltd. All rights reserved.
Napalilactone (1)1 and pathylactone A (2)2 are novel
norsesquiterpenoid spirolactones isolated from marine
sources. Their structures contain four contiguous stereo-
centers and differ only in the nature of the heteroatom
substituent (Cl versus OH) adjacent to the spirolactone
ring junction (Fig. 1). Although no biological activity
data has yet been reported for 1, pathylactone A (2)
was reported to be a Ca2+ antagonist.3 An efficient total
synthesis would provide access to these compounds for
further biological testing. The synthetic challenge pre-
sented by the stereochemically dense skeleton of 1 and
2 and our interest in spirolactones4 prompted us to
undertake their synthesis. In this Letter we describe the
preparation of ketospirolactone 10, which contains all
of the carbon atoms and three of the four stereocenters
of 1 and 2, and its diastereomer 12.
Ketone 5 (Scheme 1) was chosen as the starting point
for constructing the spirolactone moiety of the target
molecules. Unfortunately the one-pot conjugate addi-
tion of lithium dimethylcuprate to 2-methylcyclohex-2-
enone (3)5 followed by alkylation with allyl bromide
failed to provide
5 in the reported yield and
diastereomeric ratio.6,7 We then resorted to a stepwise
protocol8 in which 3 was treated with lithium dimethyl-
cuprate, and the resulting enolate was trapped with
chlorotrimethylsilane. The resulting trimethylsilyl enol
ether was isolated, and treated with methyllithium to
form the enolate that was alkylated with excess allyl
bromide to produce 5 as a 7:1 ratio of diastereomers in
51% yield for the two steps (Scheme 1). Due to the
difficulty encountered separating 5 from its anti 2,3-
dimethyl diastereomer, we explored other routes to 5.
Reduction of 2,3-dimethylcyclohex-2-enone (4)9 with
lithium in liquid ammonia, followed by monoprotona-
tion, and alkylation with excess allyl bromide gave a
10:1 ratio of 5 and its anti diastereomer in 85%
yield.10,11 Ketone 5 was separated from its diastereomer
by careful medium pressure liquid chromatography
(MPLC) on silica gel.
X
O
O
O
1
2
X = Cl
napalilactone
X = OH pathylactone A
Figure 1. Structures of napalilactone (1) and pathylactone A
(2).
Keywords: spiro compounds; lactone; sesquiterpene; natural products.
* Corresponding author. Tel.: 360-650-2883; fax: 360-650-2826;
e-mail: vyvyan@chem.wwu.edu
We next turned our attention to construction of the
spirolactone. Numerous methods for the construction
of spirolactones of the type found in 1 and 2 have been
reported.12,13 Our initial plan called for opening a
spiroepoxide intermediate with the aluminum enolate of
tert-butyl acetate.4,14 We were able to prepare the
†
This research was presented at the 37th National Organic Sympo-
sium, Bozeman, MT, June 10–14, 2001, and comprises a portion of
the M.S. thesis of C.A.R.
‡ To whom inquiries regarding the X-ray crystallographic analysis
should be addressed.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02141-4

222
J. R. Vy6yan et al. / Tetrahedron Letters 43 (2002) 221–224
O
O
a, b
OPG
OPG
OH
PGO
M
O
51 %
(7:1)
3
4
6
OH
+
3
3
c
% yield (ratio)
11 (1 : 1.2)
57 (1 : 1.2)
71 (1 : 2)
M
PG
85 %
(10:1)
7a (PG = H)
8a (PG = H)
5
6a MgCl MgCl
(+ diast.)
7b
7c
8b
8c
6b Li
6c Li
MOM
TBS
Scheme 1. Reagents and conditions: (a) (i) (CH3)2CuLi·LiBr, ether, 0°C; (ii) TMSCl; (b) CH3Li, THF, 0°C then allyl bromide; (c)
Li (2 equiv.), NH3, −78°C, H2O (1 equiv.), allyl bromide (4 equiv.).
ment was subsequently confirmed by X-ray analysis of
diastereomer 8a.24 The slight preference for formation
of 8 over 7 in these additions of can be rationalized by
axial attack of the nucleophile on the lowest energy
conformer of 5.25
required spiroepoxide from 5, but addition of the alu-
minum enolate was unsuccessful, presumably due to the
steric hindrance of the adjacent quaternary center.
We then shifted our attention to the addition of nucleo-
philes directly to the carbonyl of 5. Addition of Nor-
mant reagent 6a15 to 5 produced a 1:1.2 ratio of tertiary
alcohols 7a and 8a in a disappointing 11% yield.16 The
majority of the starting ketone was recovered, however,
leading us to suspect that enolization of 5 was to blame,
but conducting the reaction in the presence of anhy-
drous CeCl3 or excess 6a did not improve the yield.17
Alkyllithium reagent 6b18,19 improved the yield of addi-
tion product considerably, producing 7b and 8b in 57%
yield, but the diastereoselectivity of the addition was
unchanged.20 Use of 3-tert-butyldimethylsiloxypropyl-
lithium (6c)21 improved the yield further, affording 7c
and 8c in 71% yield as a 1:2 ratio of diastereomers.22
Removal of the methoxymethyl ether protecting group
present in 7b and 8b was complicated by competitive
dehydration of the tertiary alcohol under acidic condi-
tions, particularly in the case of 7b (Scheme 2). A
variety of conditions for cleaving the MOM group26
were screened before settling on those listed in Scheme
2. Tetrabutylammonium fluoride cleaved the silyl ether
groups from 7c and 8c without incident to yield the
corresponding diols 7a and 8a, respectively. Oxidation
of diol 7a with excess pyridinium dichromate27 afforded
spirolactone 928 in good yield, and 8a was converted to
spirolactone 1129 in identical fashion. Finally, Wacker
oxidation of the terminal alkene11,30 in 9 and 11 gener-
ated ketolactones 1031 and 1232 in 59 and 70% yields,
respectively. Keto lactone 10 contains all of the carbons
and three of four stereocenters found in napalilactone
(1) and pathylactone A (2).
Diastereomers 7 and 8 were easily separated in all
cases, and their relative stereochemistry was initially
assigned based on their polarity and the chemical shift
of the C(3) methine hydrogen (2.18 ppm in C6D6) in the
1H NMR spectrum of 7a, which is deshielded due a
1,3-diaxial relationship with the tertiary hydroxyl oxy-
gen in the lowest energy conformation.23 This assign-
In summary, the complete carbon skeleton of napalilac-
tone and pathylactone A has been prepared for the first
7b
a
OH
71 %
O
O
c
d
O
O
OH
b
77 %
59 %
O
90%
7c
8b
7a
9
10
O
O
e
OH
OH
O
O
76 %
c
d
75 %
70 %
b
O
70 %
8c
8a
11
12
Scheme 2. Reagents and conditions: (a) 10% HCl, THF, 42 h; (b) TBAF, THF, 0°C; (c) PDC (2.7 equiv.), CH2Cl2, 24 h; (d) CuCl
(10 mol%), PdCl2 (10 mol%), DMF, H2O, O2, 24 h; (e) conc. HCl (cat), tert-butyl alcohol, 42 h.

J. R. Vy6yan et al. / Tetrahedron Letters 43 (2002) 221–224
223
time. The synthesis covers five steps and produces keto
lactone 10 in 8% yield from 4. Diastereomeric keto
lactone 12 was produced in 15% yield from 4 using the
same sequence of reactions. Our current focus in on the
installation of the heteroatom substituent and control
of absolute stereochemistry in the preparation of 1 and
2.
hedron 1995, 51, 3389–3394; (d) Doyle, M. P.; Dyatkin,
A. B. J. Org. Chem. 1995, 60, 3035–3038; (e) Rieke, R.
D.; Sell, M. S. Xiong, H. J. Org. Chem. 1995, 60,
5143–5149; (f) Quayle, P.; Rahman, S.; Ward, E. L. M.;
Herbert, J. Tetrahedron Lett. 1994, 35, 3801–3804; (f)
Quayle, P.; Ward, E. L. M.; Taylor, P. Tetrahedron Lett.
1994, 35, 8883–8884; (g) Canonne, P.; Boulanger, R.;
Angers, P. Tetrahedron Lett. 1991, 32, 5861–5864; (h)
Black, T. H.; DuBay, W. J., III; Tully, P. S. J. Org.
Chem. 1988, 53, 5922–5927; (i) Canonne, P.; Belanger,
D.; Lemay, G.; Foscolos, G. B. J. Org. Chem. 1981, 46,
3091–3097; (j) Trost, B. M.; Bogdanowicz, M. J. J. Am.
Chem. Soc. 1973, 95, 5321–5334.
Note added in proof. The authors were alerted to a
nearly identical synthesis of spirolactone 10 carried out
by Diaz and Coelho after acceptance of this paper.33
Acknowledgements
14. Taylor, S. K. Tetrahedron 2000, 56, 1149–1163.
15. Cahiez, G.; Alexakis, A.; Normant, J. F. Tetrahedron
Lett. 1978, 3013–3014.
J.R.V. and C.A.R. thank The Camille and Henry Drey-
fus Foundation, the Western Washington University
Bureau of Faculty Research and the donors of the
Petroleum Research Fund, administered by the Ameri-
can Chemical Society, for partial support of this
research. X-ray crystallographic studies were supported
by the National Science Foundation (CHE-0078746 to
J.A.H.) and the University of Wisconsin-Eau Claire.
16. Characterization data for 7a: IR (neat) w 3380, 3072,
1
1633, 1060, and 1004 cm−1; H NMR (CDCl3, 300 MHz):
l 6.17 (dtd, J=17.2, 10.0, 5.1 Hz, 1H), 5.16 (dtd, J=
17.2, 2.1, 0.5 Hz, 1H), 5.08 (dt, J=10.0, 2.1 Hz, 1H), 3.66
(m, 2H), 2.41 (dd, J=15.3, 10.0 Hz, 1H), 2.2 (m, 3H),
1.9–1.2 (m, 11H), 0.88 (d, J=6.8 Hz, 3H), and 0.81 (s,
3H). 1H NMR (C6D6, 300 MHz): l 6.13 (dddd, J=17,
10, 9, 6 Hz, 1H), 5.05 (br d, J=17 Hz, 1H), 4.94 (br d,
J=10 Hz, 1H), 3.56 (m, 2H), 2.46 (br s, 2H,), 2.31 (dd,
J=15.3, 9 Hz, 1H), 2.18 (m, 1H), 2.07 (dt, J=15.3, 6 Hz,
1H), 1.9–1.1 (m, 10H), 0.79 (d, J=6.8 Hz, 3H), and 0.63
(s, 3H). 13C NMR (CDCl3, 75 MHz): l 138.6, 116.9, 77.8,
63.9, 39.8, 33.6, 31.7, 31.2, 30.1, 26.7, 21.1, 17.5, and
16.1. Characterization data for 8a: mp 70–73°C: IR (neat,
References
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;
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9.0, and 6.1 Hz, 1H), 5.14 (br d, J=17 Hz, 1H), 5.08 (br
d, J=10.2 Hz, 1H), 3.67 (m, 2H), 2.3–1.2 (m, 13H), 1.01
(s, 3H), and 0.87 (d, J=6.7 Hz, 3H). 13C NMR (CDCl3,
75 MHz): l 138.2, 117.0, 77.7, 63.7, 45.2, 41.4, 37.7, 30.8,
30.3, 30.2, 26.5, 22.0, 16.6, and 13.0.
Vyvyan, J. R. Synthesis 1998, 1009–1014.
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Syntheses, Coll. Vol. IV; Wiley: New York, 1963; p. 162.
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by others: Haraldsson, G. G.; Paquette, L. A.; Springer,
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17. Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima,
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18. Prepared by treating a cold (−78°C) ether solution of
3-iodo-1-methoxymethoxypropane (see Ref. 20) with tert-
butyllithium (2.1 equiv.).
19. Piers, E.; Wai, J. S. M. Can. J. Chem. 1994, 72, 146–157.
20. Characterization data for 7b: IR (neat) w 3563, 3072,
1
1633, 1148, 1038, and 918 cm−1. H NMR (CDCl3, 300
MHz): l 6.17 (dtd, J=17, 10, 5.2 Hz, 1H), 5.12 (br d,
J=17 Hz, 1H), 5.05 (br d, J=10 Hz, 1H), 4.63 (s, 2H),
3.55 (m, 2H), 3.37 (s, 3H), 2.39 (dd, J=15.3, 9.9 Hz, 1H),
2.21 (m, 2H), 1.90 (s, 1H), 1.8–1.2 (m, 10H), 0.87 (d,
J=6.9 Hz, 3H), and 0.80 (s, 3H); 13C NMR (CDCl3, 75
MHz): l 138.7, 116.4, 96.3, 77.5, 68.7, 55.1, 44.8, 39.9,
33.4, 31.7, 31.4, 30.2, 23.5, 21.2, 17.4, and 16.1. Anal.
calcd for C16H30O3 (mixture of 7b and 8b): C, 71.07; H,
11.18. Found: C, 71.06; H, 10.95. Characterization data
for 8b: IR (neat) w 3502, 3071, 1633, 1151, 1109, 1040,
10. Caine, D.; Chao, S. T.; Smith, H. A. In Organic Synthe-
sis, Coll. Vol. VI; Noland, W. E., Ed.; Wiley: New York,
1974; p. 51.
11. Srikrishna, A.; Reddy, T. J.; Nagaraju, S.; Sattigeri, J. A.
Tetrahedron Lett. 1994, 35, 7841–7844.
12. For reviews on lactone synthesis, see: (a) Collins, I. J.
Chem. Soc., Perkin Trans. 1 1999, 1377–1395; (b) Collins,
I. J. Chem. Soc., Perkin Trans. 1 1998, 1869–1888; (c)
Collins, I. Contemp. Org. Synth. 1997, 4, 281–307; (d)
Collins, I. Contemp. Org. Synth. 1996, 3, 295–321.
13. Other selected examples of spirolactone syntheses: (a)
Michaut, M.; Santelli, M.; Parrain, J. L. J. Organomet.
Chem. 2000, 606, 93–96; (b) Paruch, E.; Ciunik, Z.;
Wawrzenczyk, C. Eur. J. Org. Chem. 1998, 2677–2682;
(c) Das. J.; Choudhury, P. K.; Chandrasekaran, S. Tetra-
and 917 cm−1 1H NMR (CDCl3, 300 MHz): l 6.12
;
(dddd, J=17.2, 10.2, 9.1, 5.8 Hz, 1H), 5.09 (m, 2H), 4.62
(s, 2H), 3.56 (m, 2H), 3.38 (s, 3H), 2.3–1.2 (m, 12H), 1.02
(s, 3H), and 0.85 (d, J=6.7 Hz, 3H); 13C NMR (CDCl3,
75 MHz): l 138.3, 116.6, 96.3, 77.4, 68.5, 55.1, 45.2, 41.6,
37.6, 30.8, 30.3, 30.2, 23.4, 22.1, 16.6, and 13.1.
21. Enders, D.; Thiebes, C. Synlett 2000, 1745–1748.

224
J. R. Vy6yan et al. / Tetrahedron Letters 43 (2002) 221–224
22. Characterization data for 7c: IR (neat) w 3573, 3074,
1633, 1256, 1097, 1005, 835, and 776 cm−1 1H NMR
28. Characterization data for 9: IR (neat) w 3072, 1771, and
1635 cm−1 1H NMR (CDCl3, 300 MHz): l 5.97 (ddt,
;
;
(CDCl3, 300 MHz): l 6.16 (dtd, J=17.2, 10, 5.3 Hz, 1H),
5.11 (dtd, J=17.2, 2, 0.5 Hz, 1H), 5.02 (dt, J=10, 2 Hz,
1H), 3.65 (m, 2H), 2.38 (dd, J=15.2, 10 Hz, 1H), 2.2 (m,
2H), 1.95 (s, 1H), 1.8–1.2 (m, 10H), 0.91 (s, 9H), 0.87 (d,
J=6.9 Hz, 3H), 0.79 (s, 3H), and 0.07 (s, 6H); 13C NMR
(CDCl3, 75 MHz): l 138.8, 116.2, 77.3, 63.9, 44.8, 40.0,
33.1, 31.9, 31.5, 30.3, 26.6, 25.9, 21.2, 18.3, 17.3, 16.1,
and −5.27. Characterization data for 8c: IR (neat) w 3573,
3073, 1634, 1255, 1097, 995, 835, and 775 cm−1; 1H NMR
(CDCl3, 300 MHz): l 6.12 (dddd, J=17.1, 10.1, 9, 6 Hz,
1H), 5.07 (m, 2H), 3.65 (t, J=5.9 Hz, 2H), 2.24 (m, 2H),
1.91 (m, 1H), 1.71 (s, 1H), 1.7–1.2 (m, 10H), 1.01 (s, 3H),
0.91 (s, 9H), 0.86 (d, J=6.7 Hz, 3H), and 0.08 (s, 6H);
13C NMR (CDCl3, 75 MHz): l 138.1, 116.2, 76.4, 63.5,
44.9, 41.4, 37.4, 30.6, 30.1, 29.7, 26.1, 25.7, 21.8, 18.1,
16.4, 12.8, −5.50, and −5.52.
J=17.6, 9.4, 6.8 Hz, 1H), 4.94 (m, 2H), 2.5 (m, 3H), 2.23
(m, 2H), 2.02 (m, 1H), 1.8–1.2 (m, 7H), 0.82 (d, J=6.8
Hz, 3H), and 0.79 (s, 3H); 13C NMR (CDCl3, 75 MHz):
l 176.8, 136.3, 115.7, 91.8, 43.1, 40.5, 35.3, 34.3, 29.9,
28.8, 28.3, 21.1, 16.1, and 15.4. Anal. calcd for C14H22O2:
C, 75.63; H, 9.97. Found: C, 75.49; H, 10.23.
29. Characterization data for 11: IR (neat) w 3074, 1771 (s),
1
1636, 1217, 1168, 1001, and 921 cm−1; H NMR (CDCl3,
300 MHz): l 5.94 (dddd, J=15.0, 11.5, 9.0, 6.3 Hz, 1H),
4.85 (m, 2H), 2.57–2.18 (m, 4H), 2.02 (dd, J=15.0, 9.0
Hz, 1H), 1.9–1.1 (m, 8H), 1.05 (s, 3H), and 0.93 (d,
J=6.7 Hz, 3H); 13C NMR (CDCl3, 75 MHz): l 176.9,
136.0, 115.1, 91.8, 43.2, 36.8, 41.9, 33.7, 28.8, 28.7, 26.0,
21.0, 15.6, and 14.5. Anal. calcd for C14H22O2: C, 75.63;
H, 9.97. Found: C, 75.36; H, 10.20.
30. Tsuji, J. Synthesis 1984, 369–384.
23. (a) Paquette, L. A.; Lowinger, T. B.; Bolin, D. G.;
Branan, B. M. J. Org. Chem. 1996, 61, 7486–7491; (b)
Paquette, L. A.; Tae, J.; Hickey, E. R.; Trego, W. E.;
Rogers, R. D. J. Org. Chem. 2000, 65, 9160–9171.
24. Colorless crystals of 8a (C14H26O2) are triclinic, space
31. Characterization data for 10: mp 87–89°C; IR (KBr) w
1
1764, 1700, 1195, and 1126 cm−1; H NMR (CDCl3, 300
MHz): l 2.51 (m, 5H), 2.21 (m, 1H), 2.20 (s, 3H), 1.8–1.2
(m, 7H), 1.00 (d, J=6.9 Hz, 3H), and 0.93 (s, 3H); 13C
NMR (CDCl3, 75 MHz): l 209.0, 176.5, 90.9, 48.3, 45.7,
35.0, 33.9, 32.4, 29.9, 28.9, 28.3, 20.8, 17.0, and 15.4.
Anal. calcd for C14H22O3: C, 70.56; H, 9.30. Found: C,
70.59; H, 9.14.
(
,
group P1, with a=7.564(2), b=8.757(2), c=12.011(2) A,
h=107.97(2), i=96.59(1), k=110.92(2)°, V=683.9(3)
3
,
A , and Z=2 at 25°C. Full-matrix least-squares refine-
ment on F2 provided current residuals R1=0.0713, wR2=
0.1549, and GOF=0.972 for 1198 reflections [I>2|(I)],
and 148 variables. Data have been submitted to the
Cambridge Crystallographic Data Centre under deposi-
tion number 171156.
32. Characterization data for 12: mp 106–108°C; IR (KBr) w
1
1765, 1689, 1244, 1221, 1168, and 1143 cm−1; H NMR
(CDCl3, 300 MHz): l 2.60 (d, J=13.0 Hz, 1H), 2.52 (m,
3H), 2.35 (d, J=13.0 Hz, 1H), 2.23 (s, 3H), 2.2–1.3 (m,
8H), 1.30 (s, 3H,), and 0.86 (d, J=6.8 Hz, 3H); 13C NMR
(CDCl3, 75 MHz): l 210.1, 176.4, 91.1, 52.4, 45.5, 37.6,
32.5, 32.0, 28.6, 28.5, 25.6, 21.5, and 15.6. Anal. calcd for
C14H22O3: C, 70.56; H, 9.30. Found: C, 70.44; H, 9.49.
33. Diaz, G.; Coelho, F. J. Braz. Chem. Soc. 2001, 12,
360–367.
25. Ando, K.; Houk, K. N.; Busch, J.; Menasse´, A.; Se´quin,
U. J. Org. Chem. 1998, 63, 1761–1766.
26. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; Wiley: New York, 1999.
27. Kim, K. S.; Szarek, W. A. Carbohydr. Res. 1982, 104,
328–333.